Control over controlled radical polymerization processes

ABSTRACT

A procedure for improved temperature control in controlled radical polymerization processes is disclosed. The procedure is directed at controlling the concentration of the persistent radical in ATRP and NMP polymerizations procedures and the concentration of radicals in a RAFT polymerization process by feeding a reducing agent or radical precursor continuously or intermittently to the reaction medium through one of more ports.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/653,937, filed Dec. 18, 2009, which further claims priority under 35U.S.C. §19(e) to U.S. Provisional Application No. 61/203,387, filed Dec.22, 2008. The foregoing related applications, in their entirety, areincorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

Three controlled radical polymerization (CRP) procedures are presentlybroadly utilized for the synthesis of high performance functionalmaterials. They are: atom transfer radical polymerization (ATRP),reversible addition fragmentation transfer (RAFT) and nitroxide mediatedpolymerization (NMP). Procedures for improved levels of control overvarious CRP processes for radically (co)polymerizable monomers aredisclosed. The improvements are focused on defining industriallyscalable procedures with reduced environmental impact for the three CRPprocedures. In the case of atom transfer radical polymerization (ATRP)the improved process is conducted in the presence of low parts permillion of a transition metal catalyst complex and a high degree ofcontrol is attained by running the reaction under conditions ofcontrolled addition/activation of a reducing agent/radical initiator. Inthe case of RAFT overall control is improved by conducting the reactionunder conditions of controlled addition/activation of the radicalinitiator. The rate of polymerization in a nitroxide mediatedpolymerization (NMP) is controlled under conditions of controlledaddition/activation of a radical initiator to control the concentrationof the persistent radical.

BACKGROUND OF THE INVENTION

Many high-performance materials, particularly segmented copolymers orcomposite structures, require controlled synthesis of polymers fromfunctional monomers employing well defined initiators. [MacromolecularEngineering. Precise Synthesis, Materials Properties, Applications;Wiley-VCH: Weinheim, 2007.] For optimal performance in many applicationsthe materials also require controlled processing taking into account thesize and topology of phase separated domains and the dynamics of testingresponse rates.

Access to well-defined block copolymers was opened by Szwarc in the1950's [Nature 1956, 176, 1168-1169] by the development of livinganionic polymerization. The biggest limitation of this technique is itssensitivity to impurities (moisture, carbon dioxide) and even mildelectrophiles, which limits the process to a narrow range of monomers.The reaction medium and all components have to be extensively purifiedbefore polymerization, thus preparation of functional block copolymersor other well-defined polymeric materials in high purity can bechallenging. Nevertheless, anionic polymerization, which was firstimplemented in an academic setting, was quickly adapted on an industrialscale and ultimately led to the mass production of several well-definedblock copolymers, such as polystyrene-b-polybutadiene-b-polystyrene,performing as a thermoplastic elastomer. [Thermoplastic Elastomers, 3rdEd.; Hanser: Munich, 2004]

The fast industrial adaptation of such a challenging technique may beexplained by the fact that anionic polymerization was the first and,indeed only example of a living polymerization process for more thanthree decades, that allowed for the synthesis of previously inaccessiblewell defined high-performance materials from a very narrow selection ofvinyl monomers. Nevertheless materials based on modified blockcopolymers with properties that were desired in many applications, werethe main driving force for scaling up anionic polymerization processes.[Ionic Polymerization and Living Polymers; Chapman and Hall, New York,1993, ISBN 0-412-03661-4.]

In late 1970's to early 1990's, living carbocationic polymerization wasdiscovered and optimized. [Adv. Polym. Sci. 1980, 37, 1-144.] Howeverthis procedure is just as sensitive to impurities as anionicpolymerization and the range of polymerizable monomers for bothtechniques was essentially limited to non-polar vinyl monomers.

While many earlier attempts were made to develop controlled radicalpolymerization (CRP) processes the critical advances were made in themid 1990's. CRP can be applied to the polymerization of functionalmonomers and hence preparation of many different site specificfunctional (co)polymers under mild conditions became feasable.[Materials Today 2005, 8, 26-33 and Handbook of Radical Polymerization;Wiley Interscience: Hoboken, 2002.] From a commercial point of view, CRPprocesses can be conducted at convenient temperatures, do not requireextensive purification of the monomers or solvents and can be conductedin bulk, solution, aqueous suspension, emulsion, etc. CRP allows thepreparation of polymers with predetermined molecular weights, lowpolydispersity and controlled composition, and topology. Radicalpolymerization is much more tolerant of functional groups than ionicpolymerization processes and a broader range of unsaturated monomers canbe polymerized providing materials with site specific functionality. Inaddition, copolymerization reactions, which are generally challengingfor ionic polymerizations due to large differences in reactivity ratiosof monomers under ionic polymerization conditions, are easy to performusing radical based CRP. This provides an opportunity to synthesizepolymeric materials with predetermined molecular weight (MW), lowpolydispersity (PDI), controlled composition, site specificfunctionalities, selected chain topology and composite structures thatcan be employed to incorporate bio- or in-organic species into the finalproduct.

The three most studied, and commercially promising, methods ofcontrolling radical polymerization are nitroxide mediated polymerization(NMP), [Chemical Reviews 2001, 101, 3661-3688] atom transfer radicalpolymerization (ATRP), [J. Chem. Rev. 2001, 101, 2921-2990; Progress inPolymer Science 2007, 32, 93-146.] and degenerative transfer withdithioesters via reversible addition-fragmentation chain transferpolymerization (RAFT). [Progress in Polymer Science 2007, 32, 283-351]Each of these methods relies on establishment of a dynamic equilibriumbetween a low concentration of active propagating chains and apredominant amount of dormant chains that are unable to propagate orterminate as a means of extending the lifetime of the propagatingchains.

The simple four component atom transfer radical polymerization (ATRP)process, shown below in Scheme 1, was discovered by Matyjaszewski atCarnegie Mellon University and he and his coworkers have disclosed ATRP,and many improvements to the basic ATRP process, in a number of patentsand patent applications [U.S. Pat. Nos. 5,763,546; 5,807,937; 5,789,487;5,945,491; 6,111,022; 6,121,371; 6,124,411; 6,162,882; 6,624,262;6,407,187; 6,512,060; 6,627,314; 6,790,919; 7,019,082; 7,049,373;7,064,166; 7,157,530 and U.S. patent application Ser. No. 09/534,827;PCT/US04/09905; PCT/US05/007264; PCT/US05/007265; PCT/US06/33152,PCT/US2006/033792 and PCT/US2006/048656] all of which are hereinincorporated by reference. Based on the number of publications ATRP hasemerged as the preferred process for controlled/living polymerization ofradically (co)polymerizable monomers. Typically, an ATRP processcomprises use of a transition metal complex that acts as a catalyst forthe controlled polymerization of radically (co)polymerizable monomersfrom an initiator with one or more transferable atoms or groups.Suitable initiators are frequently substituted alkyl halides attached toa low molecular weight molecule with an additional non-initiatingfunctionality, a low molecular weight initiator or macroinitiator withtwo or more transferable atoms or groups or a solid inorganic or organicmaterial with tethered initiating groups. The transition metal catalystparticipates in a repetitive redox reaction whereby the lower oxidationstate transition metal complex (M_(t) ^(n)/Ligand) homolytically removesa transferable atom or group from an initiator molecule or dormantpolymer chain, P_(n)—X, to form the active propagating species, P^(•)_(n), in an activating reaction with a rate of activation k_(a) whichpropagates at a rate k_(p) before the higher oxidation state transitionmetal complex (X-M_(t) ^(n+1)/Ligand) deactivates the active propagatingspecies, P^(•) _(n), by donating back a transferable atom or group tothe active chain end, rate k_(da), not necessarily the same atom orgroup from the same transition metal complex. (Scheme 1)

The catalyst is not bound to the chain end, as in coordinationpolymerization, and can therefore be used in a controlled/livingpolymerization process at sub-stoichiometric amounts relative to theinitiator. Nevertheless, as a consequence of radical-radical terminationreactions, proceeding with a rate=k_(t) in Scheme 1, forming P_(n)—P_(m)dead chains and an excess of X-M_(t) ^(n+1)/Ligand.

Examples of the spectrum of new well-defined polymeric materialsprepared using ATRP in the past decade include block copolymers,branched polymers, polymeric stars, brushes, and networks, each withpre-determinable site specific functionality as well as hybrids withinorganic materials or bio-conjugates. However, its widespreadcommercial utilization is still limited. [Chem. Rev. 2007, 107,2270-2299.] Nevertheless, these custom fabricated materials havepotential to improve the performance of a multitude of commercialproducts in the areas of personal care and cosmetics, detergents andsurfactants, paints, pigments and coatings, adhesives, thermoplasticelastomers, biocompatible materials and drug delivery systems if a costeffective, environmentally benign, scalable process can be defined.

The initially defined normal ATRP process requires a high catalystconcentration, often approaching 0.1 M in bulk monomer polymerizationreactions, typical concentrations range from 0.5% to 1 mol % vs.monomer, [Handbook of Radical Polymerization; Wiley Interscience:Hoboken, 2002] to overcome the effects of continuous buildup of ATRP'sequivalent of the persistent radical (X-M_(t) ^(n+1)/Ligand). [Journalof the American Chemical Society 1986, 108, 3925-3927 and Macromolecules1997, 30, 5666-5672.] The high levels of catalyst employed in theinitial ATRP reactions, even those involving more active catalystcomplexes, were required to overcome the effects of unavoidable increasein the concentration of the higher oxidation state catalyst due tounavoidable radical-radical termination reactions. Since the finalreactor product contained between 1,000 and 10,000 ppm of the transitionmetal complex, the resulting polymer has a strong color and could bemildly toxic. This level of catalyst has to be removed from the finalpolymer prior to use in most applications. The added production costsassociated with adsorption or extraction of the catalyst in addition toisolation and recycle of organic solvents have slowed industrialacceptance of ATRP to produce materials desired by the marketplace. Anadditional problem of industrial relevance involves the use of the morerecently developed highly active (i.e., very reducing) ATRP catalysts.Special handling procedures are often required to remove all oxygen andoxidants from these systems prior to addition of the rapidly oxidizablecatalyst complex. The energy used in these purification process(es)and/or the need of rigorously deoxygenated systems contributes to thegeneration of chemical waste and adds cost. These are the major factorswhich constrain the commercial application of ATRP.

Recent advances in ATRP by the present inventors in conjunction with oneof the inventors of ATRP, K. Matyjaszewski, have been disclosed inpatent applications PCT/US2006/048656 published as WO 2007/075817,hereby incorporated by reference including further incorporation ofreferences disclosed therein to define the state of the art in ATRP anddefinitions for some of the language used herein. In that application itwas disclosed that the concentration of the catalyst used for an ATRPcan be reduced to 1-100 ppm by addition of a reducing agent, or a freeradical initiator, that acts throughout the reaction to continuouslyregenerate the lower oxidation state activator from accumulating higheroxidation state deactivator, Scheme 2. Some suitable reducing agentslisted in incorporated references include; sulfites, bisulfites,thiosulfites, mercaptans, hydroxylamines, amines, hydrazine (N₂H₄),phenylhydrazine (PhNHNH₂), hydrazones, hydroquinone, food preservatives,flavonoids, beta carotene, vitamin A, α-tocopherols, vitamin E, propylgallate, octyl gallate, BHA, BHT, propionic acids, ascorbic acid,sorbates, reducing sugars, sugars comprising an aldehyde group, glucose,lactose, fructose, dextrose, potassium tartrate, nitrites, nitrites,dextrin, aldehydes, glycine, and many antioxidants.

This improvement in ATRP was called ARGET ATRP because the Activator wascontinuously ReGenerated by Electron Transfer. In Scheme 2 theregeneration is conducted by addition of a reducing agent but thedeactivator can also be reduced by addition of a free radical initiatorin a process called ICAR (Initiators for Continuous ActivatorRegeneration) ATRP.

These novel initiation/catalyst reactivation procedures allow a decreasein the amount of catalyst needed to drive a controlled ATRP to highconversion from 10,000 ppm employed in classical ATRP to, in some cases,10 ppm or less where catalyst removal or recycling would be unwarrantedfor many industrial applications.

Furthermore ARGET/ICAR ATRP processes can start with the oxidativelystable, easy to handle and store Cu^(II) species, as it is reduced insitu to the Cu^(I) state. Furthermore, the level of control in thedisclosed ICAR/ARGET ATRP processes are essentially unaffected by anexcess (still small amount compared to initiator) of the reducing agentto continuously regenerate the lower oxidation state activator when/ifit is oxidized in the presence of limited amounts of air. [Langmuir2007, 23, 4528-4531.]

Chain-end functionality in a normal ATRP may be lost by a combination ofradical-radical termination reactions and by side reactions betweengrowing radicals and the catalyst complex; Cu^(I) (oxidation of radicalto carbocation) or Cu^(II) species (reduction of radical to carbanion).Therefore another important feature of the new ARGET/ICAR catalyticsystems is the suppression/reduction of side reactions due to the use ofa low concentration of the transition metal complex. Reducedcatalyst-based side reactions in ICAR and ARGET ATRP allow synthesis ofhigher molecular weight polymers and polymers with higher chain-endfunctionality which may allow the preparation of pure, certainly purer,block copolymers.

It was envisioned to be a simple robust procedure.

In application PCT/US2006/048656 the re-activator was added to thereaction in a single addition and control was exerted over the reactionby continuous adjustment of K_(ATRP) in the presence of excess reducingagent. Successful polymerization was achieved on the laboratory scale,10-50 mL Schlenk flasks, for common monomers such as methyl methacrylate(MMA), butyl acrylate (nBA), styrene (St) and acrylonitrile (AN). Thesuccessful synthesis of block copolymers from common monomers such asMMA, nBA, MA and St was reported.

The critical phrase in the above paragraph discloses the scale at whichthe innovative work to define the improved procedures was conducted:10-50 mL. When the procedures disclosed in PCT/US2006/048656 were scaledup some critical process disadvantages accompanying the improvementsmade in application became apparent:

-   -   a) slow reactions (especially for methacrylates, styrenes)    -   b) exothermic process (especially for acrylates) requiring    -   c) the need of precise temperature control    -   d) limited information for scale up and automation of process.

Procedures to overcome these limitations, particularly at larger scale,are disclosed herein. Indeed in one embodiment of the inventiondisclosed controlled radical polymerization processes where the rate ofaddition of a reducing agent/radical initiator is continuously adjustedallows conversion of monomer to polymer to exceed 80%, preferably exceed90% and optimally exceed 95%.

SUMMARY OF INVENTION

One embodiment of the polymerization processes of the present inventionare directed to polymerizing free radically polymerizable monomers inthe presence of a polymerization medium initially comprising at leastone transition metal catalyst and an atom transfer radicalpolymerization initiator. The polymerization medium may additionallycomprise a reducing agent or a radical initiator. Sufficient ligandshould be added to the reaction medium to modify solubility and activityof the transition metal catalyst. The one or more reducing agents orradical initiators may be added initially or during the polymerizationprocess in a continuous or intermittent manner or activated in anintermittent manner. The polymerization process may further comprisereacting the reducing agent with at least one of the transition metalcatalyst in an oxidized state further comprising a radicallytransferable atom or group to form a compound that does not participatesignificantly in control of the polymerization process. A transitionmetal in the zero oxidation state can be employed as a reducing agent.

Another embodiment of the disclosed process is directed towardscontinuous control over the concentration of the persistent radical in aNMP. In this embodiment the rate of decomposition of the initiator addedcontinuously or intermittently to the reaction is selected to match therate of radical/radical termination reactions that would otherwise buildup the concentration of the stable free radical and reduce the rate ofpropagation.

A further embodiment of the disclosed process concerns RAFTpolymerizations. In a RAFT polymerization the rate of polymerization iscontrolled by the rate of decomposition of the added initiator. Normallyall of the initiator is added to the reaction at the beginning of thereaction and this could lead to an increased rate of initiatordecomposition if the temperature of the reaction is not well controlledthroughout the polymerization vessel during each stage of the reaction.As noted for ICAR ATRP continuous addition of the initiator andmonitoring of the temperature of the reaction provides information on,if and when addition of the initiator should be stopped in order toretain control over the reaction.

Embodiments of the polymerization process of the present inventioninclude bulk polymerization processes, polymerization processesperformed in a solvent, polymerization processes conducted from solidsurfaces, biphasic polymerization process including emulsionpolymerization processes, mini-emulsion polymerization processes,microemulsion processes, reverse emulsion polymerization processes, andsuspension polymerization processes. In such biphasic polymerizationprocesses the polymerization processes may further comprise at least oneof a suspending medium, a surfactant or reactive surfactant, and amonomer phase comprising at least a portion of the radicallypolymerizable monomers.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “and,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a polymer” may include more than one polymer orcopolymers.

Unless otherwise indicated, all numbers expressing quantities ofingredients, time, temperatures, and so forth used in the presentspecification and claims are to be understood as being modified in allinstances by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the followingspecification and claims are approximations that may vary depending uponthe desired properties sought to be obtained by the present invention.At the very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, may inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

It is to be understood that this invention is not limited to specificcompositions, components or process steps disclosed herein, as such mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to be limiting.

This disclosed procedures provide a means to optimize and automate thepolymerization processes by exercising continuous control over the ratioof activator/deactivator, concentration of persistent radical orconcentration of initiator present in a CRP.

The advantages of the disclosed ‘starve feeding/activation’ methodinclude:

-   -   a) use of lower amounts of catalyst and radical initiator or        reducing agent,    -   b) reduced need for precise temperature control,    -   c) higher reaction temperature, which allows higher conversions        in a shorter time with reduced amounts of solvents,    -   d) the potential for automation of the whole process, and    -   e) the development of safe scalable processes for exothermic        polymerization reactions, although heat removal is still a        requirement.

The resulting expansion of the utilization of the proposed system forCRP will allow a reduced cost for purification of the products, asignificant decrease in waste and improve safety by providing anadditional means to control reaction temperature. Furthermore the rateof addition of a reducing agent/radical initiator can be continuouslyadjusted to allow the conversion of monomer to polymer to exceed 80%,preferably exceed 90% and optimally exceed 95% by taking intoconsideration the viscosity of the reaction medium and the rate ofdiffusion of the added reducing agent.

In the following examples, and discussion of examples, ATRP is employedas an exemplary CRP but the disclosed procedures can be applied to NMPand RAFT as indicated above.

BRIEF DESCRIPTION OF THE FIGURES

The following figures exemplify aspects of the disclosed process but donot limit the scope of the process to the examples discussed.

FIG. 1. Variation of temperature inside a 1 L batch reactor during ARGETATRP of nBA. Experimental conditions:nBA/DEBMM/CuBr₂/TPMA/Sn(EH)₂=500/1/0.025/0.1/0.1, in bulk at 60° C.

FIG. 2. Parameters employed for the computer simulation of thepolymerization of MMA under a series of reaction conditions. Thepurpose: to find optimal conditions for new feeding method. Results:models were built and successful simulations were performed and optimalconditions were found. Concerns: heat transfer, side reactions, catalyststability, etc. not taken into account.

FIG. 3A. Simulated kinetics plot.

FIG. 3B. Simulated molecular weight and PDI vs. conversion.

FIG. 3C. Simulated GPC trace.

FIG. 4A. Molecular weight and PDI vs. conversion for example C1.

FIG. 4B. GPC curves for example C1.

FIG. 5A. Molecular weight and PDI vs. conversion for example C2.

FIG. 5B. GPC traces for example C2.

FIG. 6A. Molecular weight and PDI vs. conversion for example C3.

FIG. 6B. GPC curves for example C3.

FIG. 7A. Molecular weight and PDI vs. conversion for example C4.

FIG. 7B. GPC curves for example C4.

FIG. 8A. Kinetics plot for example C5.

FIG. 8B. Molecular weight and PDI vs. conversion for example C5.

FIG. 8C. GPC curves for example C5.

FIG. 8D. Temperature profile for example C5.

FIG. 9. Polymerization of MMA targeting low degree of polymerization,wherein:

FIG. 9A is the kinetic plot;

FIG. 9B shows the molecular weight and PDI vs. conversion; and

FIG. 9C is the GPC traces for ICAR ATRP of MMA with feeding of AIBN(experiment 08-006-165). Conditions:MMA/DEBMM/CuBr₂/TPMA/AIBN=100/1/0.005/0.025/−; in bulk [MMA]=8.9 mol/L,50 ppm of Cu, T=90° C. Feeding rate slow: 0.002 mol equivalent of AIBNvs. DEBMM in 1 h (AIBN in 40 ml of solvent to 850 ml of the reactionsolution).

FIG. 10. Polymerization of MMA targeting high degree of polymerization,wherein:

FIG. 10A is a kinetic plot;

FIG. 10B shows the molecular weight and PDI vs. conversion; and

FIG. 10C is the GPC trace for ICAR ATRP of MMA with feeding of V-70(experiment 08-006-180). Conditions: MMA/DEBMM/CuBr₂/TPMA/V-701000/1/0.05/0.1/−; in bulk [MMA]=8.9 mol/L, 50 ppm of Cu, T 80° C.Feeding rate slow: 0.004 mol equivalent of V-70 vs. DEBMM in 1 h (V-70in 40 ml of solvent to 850 ml of the reaction solution).

FIG. 11. Computer simulation of polymerization of n-butyl acrylate,wherein:

FIGS. 11 A-C) are with feeding of AIBN; and

FIGS. 11 D-F) are without feeding of AIBN. Conditions for ICAR ATRP ofnBA with feeding of AIBN: nBA/DEBMM/CuBr₂/TPMA/AIBN=100/1/0.005/0.005/−;in bulk [nBA]=7.0 mol/L, 50 ppm of Cu, T=90° C. Feeding rate fast: 0.03mol equivalent of AIBN vs. DEBMM in 6 h (AIBN in 90 ml of solvent to 1 Lof the reaction solution). Comments: simulated polymerization reached99.2% conversion in 1.7 h (PDI=1.13; chain-end functionality=99%); thereis a short indiction period but reaction was very fast and wellcontrolled; amount of AIBN added after 1.7 h was 0.0086 mol equivalentsvs. initiator. Conditions for ICAR ATRP of nBA without feeding of AIBN:nBA/DEBMM/CuBr₂/TPMA/AIBN=100/1/0.005/0.005/0.03; in bulk [nBA]=7.0mol/L, 50 ppm of Cu, T=90° C. Comments: simulated polymerization reached99.2% conversion in 28 minutes (PDI=1.38; chain-end functionality=99%);polymerization was extremely fast and resulted in polymer withrelatively broad molecular weight distribution (PDI=1.6-2.2 for lowerconversions).

FIG. 12A. Kinetics plot for example 2A.

FIG. 12B. Molecular weight and PDI vs. conversion for example 2A.

FIG. 12C. GPC curves for example 2A.

FIG. 12D. Temperature profile for example 2A.

FIG. 13A. Kinetics plot for example 2B.

FIG. 13B. Molecular weight and PDI vs. conversion for example 2B.

FIG. 13C. GPC curves for example 2B.

FIG. 14. Temperature profile for run 08-006-194.

FIG. 15. ICAR polymerization of styrene, wherein:

FIG. 15A is the kinetic plot;

FIG. 15B shows the molecular weight and the PDI vs. conversion; and

FIG. 15C is the GPC traces for ICAR ATRP of St with feeding of AIBN(experiment 08-006-192). Conditions: St/DEBMM/CuBr₂/TPMA/AIBN100/1/0.005/0.1/0.005; in bulk [St]=8.31 mol/L, 50 ppm of Cu, T=100° C.Feeding rate slow: 0.008 mol equivalent of AIBN vs. DEBMM in 1 h (AIBNin 40 ml of solvent to 850 ml of the reaction solution).

FIG. 16. Polymerization of St (high DP). Automation of process. ICARATRP of St with feeding of AIBN (experiment 08-006-193), wherein:

FIG. 16A is the molecular weight and PDI vs. conversion; and

FIG. 16B is the temperature profile. Conditions:St/DEBMM/CuBr₂/TPMA/AIBN 1000/1/0.05/0.15/0.025; in bulk [St]=8.31mol/L, 50 ppm of Cu, T=100-110° C. Feeding rate slow: 0.008 molequivalent of AIBN vs. DEBMM in 1 h (AIBN in 40 ml of solvent to 850 mlof the reaction solution).

FIG. 17. Kinetics for ICAR ATRP of St with feeding of AIBN (experiment08-006-193) targeting high DP, wherein:

FIG. 17A is the molecular weight and PDI vs. conversion; and

FIG. 17B is the GPC curves. Conditions:St/DEBMM/CuBr₂/TPMA/AIBN=1000/1/0.05/0.15/0.025; in bulk [St]=8.31mol/L, 50 ppm of Cu, T=100-110° C. Feeding rate slow: 0.008 molequivalent of AIBN vs. DEBMM in 1 h (AIBN in 40 ml of solvent to 850 mlof the reaction solution).

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

As noted above even though ICAR and ARGET ATRP were successfully appliedto the preparation of polymeric materials on the laboratory scale,unexpected problems were encountered when larger scale synthesis wereconducted. These problems are exemplified by the following discussioninvolving scaling-up the ICAR system but are also relevant for ARGETATRP, RAFT and NMP systems.

-   -   a) Precise temperature control throughout the reaction medium is        required—if this is not achieved, an increase in temperature        will cause the radical initiator which is present in the system        to decompose at a faster rate and reduce all Cu^(II) to Cu^(I)        species. The loss of Cu^(II) deactivator from the system results        in an uncontrolled polymerization in addition to a temperature        exotherm. Moreover control over temperature in an exothermic        polymerization reaction is challenging in large scale        polymerization procedures due to inefficiencies in heat transfer        processes in increasingly viscous media. In standard free        radical polymerization systems viscous polymer solutions can        lead to the Trommsdorf effect.    -   b) FIG. 1 presents a temperature profile that follows the        reaction temperature during the polymerization of nBA using        ARGET ATRP on a 1 liter scale. The stirred reaction mixture was        heated to 60° C., but due to the exothermic polymerization        process the temperature inside the flask increased above 80° C.        The polymerization was not well controlled due to overheating.        This indicates that the use of internal cooling (e.g., a cooling        coil) may not be efficient enough to uniformly keep the        temperature within a 2-3° C. temperature range.    -   c) Long reaction times:—due to lower temperatures used in the        publications discussing ICAR/ARGET, and other CRP systems. Lower        temperatures are targeted to allow a slow generation of radicals        (ICAR) or slow reaction of the added reducing agent with the        Cu^(II) complex that had been added at the beginning of the        reaction resulting in reaction times that are longer than        desired for an economic industrial process.    -   d) Lower temperatures also increase the viscosity of the system        and limit the range of monomers that can be polymerized to high        conversion, for example monomers that form polymers with a glass        transition temperature, Tg, close to or below the reaction        temperature reach a glassy state at high conversion and control        is lost    -   e) Lack of easy automation of the whole process—as FIG. 1        illustrates there is no easy way to automate the ICAR/ARGET ATRP        with the current experimental setup and the presence of an        excess of radical initiator requires good temperature control.    -   f) Although small amounts of catalyst and radical initiator (or        reducing agent) are used, a further reduction of the amount of        copper catalyst and radical initiator is still desired.    -   g) Limited accessible molecular weights (MW) of the polymer. For        many applications, it is essential to prepare high MW polymers;        i.e., polymers with segments above the chain entanglement MW,        therefore it is very important to minimize the effect of “side”        reactions between the growing radicals and the catalyst that        limit the attainable MW. ARGET and ICAR techniques can partially        solve this problem due to the use of low catalyst concentration        but the problems noted above with side reactions associated with        transition metal, ligand and reducing agent have to be resolved        by further reducing the concentration of one or more of the        reagents.

The new disclosed method will alleviate/resolve all of the above statedlimitations.

The new method relies on precise continuous control of theCu^(II)/Cu^(I) ratio during an ICAR/ARGET ATRP, or instantaneousconcentration of radicals in RAFT polymerization, or targetedconcentration of the persistent radical present in an NMP process, byfeeding a radical initiator (or reducing agent) to the polymerizationmixture at a controlled rate and optionally using multiple additionports to evenly distribute the agent throughout the whole reactionmedium. Feeding should occur at a such a rate that the amount of radicalinitiator (or reducing agent) added or generated can properly compensatefor all the termination reactions that had occurred since the lastaddition and convert only the appropriate amount of Cu^(II) to Cu^(I)(Scheme 3a). Therefore, the amount of added radical initiator, orreducing agent, at any time of feeding should approximately equal to thenumber of terminated chains (Scheme 3b) formed since the previousaddition.

As disclosed herein if the initiator or reducing agents are slowly addedthroughout the reaction the amount of “excess” activator is controlledand any increase in the rate of decomposition or reduction is avoided.If the reaction temperature should rise stopping addition eventuallystops the reaction. Suitable reducing agents are disclosed inincorporated references.

In contrast to the present ARGET and ICAR procedures the amount ofinitiator added in a single addition should be less than thestoichiometric amount required to reduce all of Cu^(II) present in thereactor to Cu^(I). This will be accomplished by the presence, oractivation, of a very small amount of residual initiator (or reducingagent) in the reactor at any time. The amount of initiator fed to thereactor, or generated, should match the amount of termination thatoccurs since the previous addition/activation. If temperature wouldlocally increase, due to a poor heat exchange or local overheating, theexcess reduction of Cu^(II) to Cu^(I) is thereby easily contained andlimited to only the amount of initiator locally present in the reactionmedium. Thus, instead of adding the entire amount initiator/reducingagent at the beginning of the reaction and counting on fortuitouscontrol over the rate of decomposition of the initiator to maintaincontrol, only as much reducing agent/initiator as needed will be fed tothe system, or instantaneously generated, during the entire processwhile limiting the effect of temperature fluctuations on the rate ofreduction of Cu^(II) to Cu^(I).

If such conditions are fulfilled, ‘starving conditions’ for reducingagent or radical initiator during polymerization process will beachieved and will result in the desired constant Cu^(II) to Cu^(I)ratio. A sufficiently high amount of Cu^(II) is a requirement forproduction of (co)polymers with narrow molecular weight distribution ina controlled ATRP process, equation 1.

$\begin{matrix}{\frac{M_{w}}{M_{n}} = {1 + \frac{1}{{DP}_{n}} + {( \frac{\lbrack {R - X} \rbrack_{o}k_{p}}{k_{da}\lbrack {X - {Cu}^{II}} \rbrack} )( {\frac{2}{p} - 1} )}}} & 1\end{matrix}$

In one embodiment of the process after the desired ratio ofCu^(II)/Cu^(I) is attained only a very small amount of radical initiator(or reducing agent) will be instantaneously present in any volumefraction of the polymerization system. As a result, the ratio ofCu^(II)/Cu^(I) will be kept within the appropriate range to producepolymers with narrow molecular weight distribution, equation 1.

Several advantages accrue from the new ‘feeding’ method as a result ofkeeping the instantaneous concentration of radical initiator (or otherreducing agent) very low in the polymerization system.

-   -   a) No need of precise temperature control—the only requirement        will be to keep the temperature high enough to quickly decompose        the added radical initiator, while still allowing sufficient        time for distribution of the initiator throughout the targeted        volume of the reaction mixture after addition. Multiple addition        ports can be used for larger scale industrial equipment to        minimize the time required for diffusion of the activator to all        parts of the reaction medium or only sufficient light to        decompose the required amount of photo-responsive initiators is        pulsed into the reactor.    -   b) Safe process for exothermic reactions—the effect of an        exothermic reaction will be diminished by very low instantaneous        concentration of radical initiator (or reducing agent) since the        added tiny amount of initiator/reducing reagent cannot overwhelm        the excess Cu^(II) present in the reactor. This means that in        the absence of added initiator/activator only a controlled ATRP        reaction can occur and this reaction will slow down if an        increased concentration of Cu^(II) is generated by termination        reactions since excess Cu^(II) acts to increase the rate of        deactivation of any growing radical chains.    -   c) Shorter reaction times—due to the use of higher reaction        temperatures, reactions can be much faster since the rate        constant of propagation increases with temperature much more        than that of termination thereby retaining a high mole fraction        of “living” chains. Higher reaction temperature also results in        lower viscosity systems at any particular conversion and hence        the reaction can be driven to higher conversion as well as        preparation of higher molecular weight polymers. The conversion        of monomer to polymer can therefore exceed 80%, preferably        exceed 90% and optimally exceed 95%.    -   d) Full automation possible—as only tiny amounts of radical        initiator (or reducing agent) are present at any instant in the        polymerization medium, the reaction should stop as soon as        feeding/activation is stopped. Thus, the rate of polymerization        is controlled by the rate of generation of radicals by        decomposition of the radical initiator (or by the concentration        of reducing agent) and is stopped in any emergency conditions        simply by incorporating a feedback loop that stops addition of        radical initiator, reducing agent or activation of an added        photo-responsive initiator.    -   e) Continuous feeding of initiator/reducing agent in order to        minimize steady state residual concentration of the radical        initiator thereby reducing initiator based side reactions.    -   f) Lower amounts of transition metal and ligand are required in        the reaction. An excess of ligand is normally used in ARGET and        ICAR polymerizations to counteract possibility of formation of a        monomer/transition metal complex.    -   g) Possible control over PDI by increasing the Cu^(I)/Cu^(II)        ratio and k_(p), which depends on monomer type and temperature.    -   h) One pot synthesis of block copolymers since higher chain end        functionality is retained.        Abbreviations Used in the Following Examples:

ATRP atom transfer radical polymerization

ARGET activator regenerated by electron transfer

ICAR initiator for continuous activator regeneration

DEBMM diethyl 2-bromo-2-methylmalonate

BrPN 2-bromopropionitrile

TPMA tris(2-pyridylmethyl)amine

AIBN 2,2′-azobis(2-methylpropionitrile

V-70 2,2′-azobis(4-methoxy-2.4-dimethyl valeronitrile)

EXAMPLES AND DISCUSSION OF EXAMPLES

During the initial attempts to scale up ARGET/ICAR ATRP detailed belowit became clear that the number of variables that have to be controlledare significantly greater than initially expected as the scale of thereactions was increased. Therefore in order to define optimalpolymerization conditions for the new ‘feeding’ methods for ICAR ATRP,it was crucial to generate a set of parameters for the feeding rate ofradical initiator that takes into account the specific type of monomer,reaction temperature, type of radical initiator, concentrations andratios of all reagents, etc. Kinetic modeling was conducted to selectinitial conditions to reach synthetic targets and understand factorsaffecting control under many different conditions. In addition, someadditional parameters such as rate of diffusion of the initiator fed tothe solution, heat transfer related to the reactor design, viscosity ofpolymer solution at know conversion and others were taken into account.

The potential starting points generated by computer modeling of thecritical process factors were investigated by performing experiments on1 L scale with a single source of added reducing agent. All of thesefactors were carefully studied to achieve good control over thepolymerization process and to provide the kinetic data required forfurther scale up to industrial scale equipment.

Computer Simulations

The synthetic conditions of the new ‘feeding’ method for ICAR ATRP weremodeled via computer. Comparable software has been successfully appliedto many polymerization systems including normal and ICAR ATRP[Macromolecules 2007, 40, 6464-6472.] and allows precise calculation ofthe concentration of all species (including intermediates) in a reactionversus time or conversion. It also permits one to estimate the molecularweight distributions of all polymeric species. All required parameterssuch as rate constants, initial concentrations of all reactant and therate of feeding of radical initiator are entered in the workshopassistant of the software. Computer simulations are simple to performand can be completed in a short period of time, thus a broad range ofdifferent variables can be studied to optimize the new ‘feeding’ methodfor an exemplary ICAR ATRP. Typical variations for specific monomers arediscussed below. In ICAR it is crucial to correlate feeding/generationrate of the radical initiator (RI) with other parameters (temperature,type of radical initiator, etc.) in order to obtain good control overthe polymerization process.

Computer Simulations for Polymerization of Methyl Methacrylate

FIG. 2 shows the initial set of parameters used for computer simulationsconducted for polymerization of MMA with continuous feeding of twodifferent radical initiators at a series of temperatures targetingdifferent DP. Preliminary results from initial simulation of theproposed method suggested that this approach to process conditionevaluation is possible.

The general ratio of reagents for one exemplary non-limiting example ofthe new ‘feeding’ method for ICAR ATRP with 50 ppm amount of Cu was:M/R—X/CuBr₂/ligand/RI=X/1/0.01/0.01/0.05 in bulk at temperature T (whereM—monomer, R—X—alkyl halide initiator, RI—radical initiator, X=100,500). Commercially available tris(2-pyridylmethyl)amine (TPMA) was usedas the initial exemplary ligand and diethyl 2-bromo-2-methylmalonate(DEBMM) was used as an exemplary alkyl halide initiator in thepolymerization systems. Other catalysts and initiators were alsoevaluated. The RI was fed to the reaction medium at two different ratesand the targeted reaction time was set for either 6 or 24 hours.

Therefore the initial set of simulations for polymerization of MMA usingthe new ‘feeding’ method were conducted with 50 ppm amount of Cu and theratio of reagents: MMA/DEBMM/Cu^(II)Br₂/TPMA/RI=X/1/0.01/0.01/0.05 inbulk. Two different radical initiators were used,2,2′-azobis(2-methylpropionitrile) (AIBN), with a 10 hour half-lifedecomposition temperature at 65° C.) and2,2′-Azobis(4-methoxy-2.4-dimethyl valeronitrile) (V-70), with a 10 hourhalf-life decomposition temperature at 30° C.). Different temperatureswere applied for polymerizations with AIBN (70, 80, 90° C.) and V-70(45, 55, 70° C.) as radical initiators. They provide half-lifedecomposition times of 300, 70, 20 minutes, and 60, 15, 3 minutes,correspondingly. Two different degrees of polymerizations will be chosen(DP=X=100, 1000) in order to cover a typical range of molecular weightsaccessible with the new method. The feeding rate of the radicalinitiator will be set for 6 and 24 h as a final time.

The overall volume of the solution of radical initiator that was fed tothe reaction was less than 10% versus volume of monomer (reactionvolume), i.e., while dilute solutions of the initiator were added thetotal added solvent will be within limits associated with “monomer”removal from a bulk polymerization. The final objective was to provideconditions for polymerization of a range of methacrylate monomers.

It is expected that a broad range of type I and type II photoinitiatorscan be employed and simulations will examine the effects of therate/intensity of stimulation.

Other simulations designed to provide starting conditions forpolymerization reactions examined periodic addition/formation of radicalinitiators or reducing agents for transition metal complexes studied arange of parameters including:

-   -   type of monomer (different rate constants of propagation and        termination as well as activation and deactivation will be        applied to different types of monomers and catalysts). Styrene,        n-butyl acrylate and methyl methacrylate were the initial three        exemplary monomers as they cover the three largest classes of        radically polymerizable monomers.    -   Type of radical initiator (different rate constants of        decompositions, also depending on temperature).    -   Type of catalyst (different rate constants of activation and        deactivation).    -   Degree of polymerization (DP) (both low and high MW).    -   Temperature (change of decomposition rates of radical initiator        and all other rate constants).    -   Rate and method of feeding for the radical initiator/activator        (slow, fast and periodical).

Other parameters such as ratios and concentrations of reagents wereinitially kept constant but later were also varied in order to minimizethe amount of copper and initiator and optimize polymerization rate.

FIGS. 3A, 3B and 3C show the simulated kinetic plot, molecular weightand polydispersity (PDI) vs. conversion and GPC trace of PMMA preparedvia the feeding method for ICAR ATRP, respectively. The results shown inFIG. 3 are for simulations done for experimental conditions:MMA/DEBMM/Cu^(II)Br₂/TPMA/AIBN=500/1/0.025/0.025/0.05 in bulk at 90° C.,with a constant concentration of initiator added over a feeding time 10h. The linear kinetics, good control over molecular weight, low PDI andmonomodal distribution of molecular weight show that the polymerizationcould be well controlled.

A series of simulations were conducted using methyl methacrylate, butylacrylate and styrene as exemplary monomers. The results from the initialseries of simulations for these three monomers provided starting pointsfor reactions conducted in a 1 L reactor. Based on the experimentalresults, some additional changes can be made in the simulation to fullyoptimize the investigated polymerization system.

A similar series of simulations will be conducted using aphotoresponsive initiator to determine if the rate of radical formationcan be controlled by controlled photostimulation.

A similar series of simulations will be conducted using a reducing agentto determine if ARGET ATRP con be conducted under “starved” feedingconditions and result in improved control.

Polymerization Experiments

Polymerization experiments using the new ‘feeding’ method for ICAR ATRPwere carried out for three representative monomers (MMA, nBA and St) ata 1 liter scale in a Ace Glass reactor equipped with a heating mantle,mechanical stirrer and thermocouple. At this scale of the reaction,challenges related with heat transfer and viscosity, as well asexothermicity, become important; as discussed the background section andshown in FIG. 1. These factors are not taken into account by computermodeling software. Thus, some adjustments were made in order to fullyoptimize the new ‘feeding’ method in the actual ICAR ATRP experimentalexamples.

Nonetheless, initially each monomer was polymerized with the conditionsinitially optimized via computer simulations. Additional adjustmentswere made in order to further increase control over the polymerization.These adjustments are specified for each monomer below.

The run numbers listed below were employed for internal tracking of theexperiments and do not have any further significance.

Comparative Example C1

ARGET ATRP of MMA with Sn(EH)2 as reducing agent: Run 07-004-83. Scale:in 1 L reactor. Conditions:MMA/DEBMM/CuBr₂/TPMA/Sn(EH)₂=2200/1/0.015/0.06/0.1 in DMF (0.05 volumeeq. vs. MMA), (7 ppm of Cu), T=65° C.

The polymerization was performed in bulk and at 65° C. The reaction waswell controlled with Mn close to theoretical values and low PDI. Thekinetics of the reaction and GPC results of the polymer samples takenduring the experiment are shown in FIGS. 4A and 4B. After 27.6 hours thefinal degree of polymerization (DP) of the polymer was 890 and theM_(n(GPC))=90,000 with a polydispersity of 1.17. A small tailing to thelow molecular weight is visible on GPC traces.

Comparative Example C2

Chain extension of polymer prepared in example C1: Run 07-004-84. Scale:25 mL Schlenk flask. Conditions:St/PMMA/CuBr₂/TPMA/Sn(EH)₂=5000/1/0.02/0.06/0.2 in anisole (0.1 volumeeq. vs. St), (4 ppm of Cu) T=80° C. (07-004-83 as macroinitiator)

The kinetics of the reaction and GPC results of the experiment are shownin FIGS. 5A and 5B. The GPC results of the polymer samples taken duringthe experiment indicates that the chain extension of the PMMAmacroinitiator formed in example C1 with St was not fully successful.One can conclude that despite the narrow PDI of the macroinitiator thechain-end functionality is not very high, after 4000 minutes reactionsome of macroinitiator was still not chain extended resulting in bimodalmolecular weight distribution.

One reason for low chain-end functionality is a transfer reaction of thegrowing radical to Sn(EH)₂ indicating that a different reducing agenthas to be used in order to synthesize PMMA with high molecular weightand high chain-end functionality.

Comparative Example C3

ICAR ATRP of MMA with AIBN as radical initiator. Run: 07-004-85. Scale:1 L reactor. Conditions:MMA/DEBMM/CuBr₂/TPMA/AIBN=2400/1/0.02/0.025/0.15 in anisole (0.03 volumeeq. vs. MMA), (8 ppm of Cu), T=55° C.

The kinetics of the reaction and GPC results of the polymer samplestaken during the experiment are shown in FIGS. 6A and 6B. In thiscomparator example polymerization of MMA was performed in bulk at 55° C.in the presence of AIBN instead of Sn(EH)₂ to avoid transfer reactionsto Sn(EH)₂ apparent during the chain extension reaction described inexample C2. After 45.5 hours reaction the DP of the polymer was 894 andthe MW 89,500 with M_(n) close to theoretical values and low PDIindicating the polymerization was well controlled. No tailing is visibleon GPC traces suggesting that no transfer reactions occurred during thepolymerization process.

Comparative Example C4

Chain extension of polymer prepared in example C3. Run: 07-004-89.Scale: 25 mL Schlenk flask. Conditions:St/PMMA/CuBr2/TPMA/Sn(EH)₂=5000/1/0.02/0.06/0.2 in anisole (0.1 volumeeq. vs. St), (4 ppm of Cu), T=80° C., time=40.2 hr. Sample C3, 07-004-85as macroinitiator

The kinetics of the reaction and GPC results of the polymer samplesduring experiment are shown in FIGS. 7A and 7B. The chain extension ofPMMA C3 with St was successful. Chain-end functionality of PMMA C3 ismuch higher than in PMMA C1, no bimodal distribution of molecular weightwas observed after extension, only small tailing visible on GPC tracesof the polymer samples taken during the experiment. This result provesthat one reason of low chain-end functionality of PMMA C1 is thetransfer reaction to Sn(EH)₂. Indicating that either ICAR ATRP or anon-transition metal based reducing agent has to be used in order toobtain PMMA with higher chain-end functionality.

Comparative Example C5

ICAR ATRP of MMA with AIBN as radical initiator. Run: 08-006-48. Scale:in 1 L reactor. Conditions:MMA/DEBMM/CuBr2/TPMA/AIBN=2400/1/0.025/0.03/0.2 in bulk (anisole asinternal standard), (10 ppm of Cu), T=55° C., time=41.6 hours.

The kinetics of the reaction and GPC curves of the polymer samples takenduring the experiment are shown in FIGS. 8A and 8B, indicating that thefinal polymer had a DP of 1414 and M_(n(GPC)) 141,600. Thepolymerization was well controlled at the beginning. The final PDI,sample 3 was slightly higher than sample 2, but significant temperaturefluctuations were encountered when higher conversion was attempted whichindicates that the flask had been heated for too long resulting in anuncontrolled polymerization. This is a consequence of the high viscosityof the solution of the glassy polymer at low temperatures. Although highmolecular weight was reached, chain-end functionality may be low due tooverheated polymerization solution resulting in solid glassy polymer anda broken stirring rod.

Example 1 Polymerization of Methyl Methacrylate (MMA)

Polymerization of MMA was carried out first using the new ‘feeding’method for ICAR ATRP. The best polymerization conditions were chosenfrom the computer modeling and tested in a 1 liter scale reactor. Thetemperature inside the reactor was followed using a thermocouple with asecond thermocouple located outside the reactor, between the wall of thereactor and the heating mantle to provide additional information of thelevel of temperature control attained in the reaction. The difference intemperature between the two thermocouples can be related to theefficiency of heat transfer in this system. The efficiency of heattransfer may change significantly with viscosity and will affect thecontrol of polymerization.

Another factor which computer modeling does not take into account is therate of diffusion of the radical initiator after feeding into a viscoussolution. The radical initiator should be evenly distributed beforesignificant decomposition occurs. In order to investigate that, atdifferent stages of the polymerization (when solution will becomeprogressively more viscous), a colored dye will be injected and a timeof its distribution will be evaluated (visually and/orspectroscopically). The results of this study will provide informationon the distribution of injection sites required for optimal control in alarge scale reactor.

Polymerization of MMA Using the Proposed Method

The results of the computer simulations were used as starting points for10 test reactions. It was determined that an excess of ligand had to beused in order to get a controlled polymerization. Polymerizationsrevealed linear kinetics and molecular weights were close to theoreticalvalues. However, when targeting low DP the PDI's remained quite broad,FIG. 9. Additional reactions were then performed to optimize synthesisof PMMA using the disclosed feeding method. The results and observationsduring the initial experiments indicated that the reason for poorresults, broad PDI, is very low initiation efficiency of DEBMM in theICAR ATRP system, a signal from the initiator was visible on GC traceseven after several hours of reaction. For high DP polymers molecularweights were lower than theoretical values and PDI initially decreasedwith conversion but increased at high conversion, FIG. 10. Anotherobservation was that the polymerization mixture was becoming cloudy withreaction time. This is probably the reason for loss of the control atthe end of most of the polymerization reactions. It was determined thatthe selected ATRP initiator (DEBMM) was mostly responsible for sidereaction and destabilization of the very low concentration of coppercatalyst.

Therefore a more efficient initiator, BrPN, was tested in ICAR ATRP withfeeding of AIBN and good results were obtained.

After performing the first reactions with MMA, the experimental and thesimulated results were compared. Differences can be attributed toeffects of heat transfer, viscosity, initiator diffusion, impurities,and the amount of air in the system. These observations indicate thatthe reactor should be equipped with a mechanical stirrer. In order tofurther reduce problems related to diffusion and heat transfer,reactions can be diluted (with monomer or solvent) and stopped at lowerconversions (unreacted monomers (diluents) can be recovered and reused).Additional experiments were conducted in order to optimize the reactionconditions at this scale with a single source of added initiator. Theparameters that were adjusted include: temperature, targeted DP, feedrate of radical initiator, concentration of reagents, and amount of Cucatalyst.

Example 2 Polymerization of n-Butyl Acrylate

Computer Simulations for Polymerization of n-Butyl Acrylate

A computer model similar to that shown in FIG. 2 was built and thenpolymerization simulations were performed for n-butyl acrylate (nBA).The main goal of the simulations was to find starting conditions forreal polymerization experiments by varying several different parametersin the software; type of radical initiator, degree of polymerization DP,feeding rate of radical initiator.

One of the goals for new polymerization method with controlled feedingof the initiator/activator was to make polymerization reactions as fastas possible and at the same time still have a controlled process. As inthe case of PMMA, evaluation of simulated results for PnBA was based onthese factors and new evaluation scale was introduced. The scale wasslightly different than that for MMA due to relatively faster reactionsfor nBA type monomer.

Relative Control Scale Description

Very good: conversion >99% after less than 6 hours reaction and PDI<1.15and functionality>98%, with linear kinetics.

Good: conversion=95-99% after less than 10 hours reaction orPDI=1.15-1.20 or functionality=95-98%,

Intermed.: conversion=80-95% after less than 20 hour PDI=1.20-1.25 orfunctionality=85-95%,

Poor: conversion<80% after less than 20 hour or PDI>1.25 orfunctionality<85%.

All rates and rate constants were adjusted for each simulatedpolymerization as reported in Table 1 presented below.

TABLE 1 Relative Conv. Time Funct. Exp. control [%] [h] PDI [%] Comments25 Good 99.2 1.7 1.13 99 Induction period was observed 25a Poor 99.2 0.51.38 99 High PDI 25b Very good 99.2 1.2 1.15 99 Very short inductionperiod was observed 26 Good 99.2 3.3 1.14 99 Induction period wasobserved 27 Good 99.2 2.6 1.12 99 Induction period was observed 28 Good99.2 4.8 1.09 99 Induction period was observed 29 Good 99.2 4.3 1.11 99Induction period was observed 30 Intermediate 99.2 7.5 1.08 99 Inductionperiod was observed 31 Good 99.2 4.5 1.07 99 Induction period wasobserved 31a Poor 99.2 0.9 1.38 97 High PDI 32 Intermediate 99.2 11.31.04 99 Induction period was observed 32b Intermediate 99.2 1.4 1.21 98Medium PDI 33 Good 99.2 6.0 1.07 99 Induction period was observed 34Intermediate 99.2 13.4 1.04 99 Induction period was observed 35 Poor45.5 6.0 1.09 99 Slow reaction 36 Intermediate 99.2 18.6 1.04 99Induction period was observed 37 Good 99.2 1.9 1.16 99 Induction periodwas observed 38 Good 99.2 4.1 1.10 99 Induction period was observed 39Good 99.2 2.9 1.18 99 Induction period was observed 40 Good 99.2 5.71.11 99 Induction period was observed 41 Good 99.2 4.2 1.19 99 Inductionperiod was observed 42 Good 99.2 7.8 1.12 99 Induction period wasobserved 43 Good 99.2 4.9 1.09 99 Induction period was observed 44Intermediate 99.2 12.8 1.04 99 Induction period was observed 45 Good99.0 6.0 1.11 98 Induction period was observed 46 Intermediate 99.2 14.91.05 99 Induction period was observed 47 Good 92.4 6.0 1.12 99 Inductionperiod was observed 48 Intermediate 99.2 17.8 1.06 99 Induction periodwas observed

In almost all cases resulting polymers had low PDI, high chain-endfunctionality and molecular weights close to theoretical values. Highpolymerization rates were observed for most of the reactions (even forhigh DP) and that's why most of simulations are rated here as good sincenon-linear kinetics were observed. In conclusion simulations forpolymerization of nBA using new ‘feeding’ method were successful andoptimal conditions were found; e.g. Simulations 25, 25b, (see FIG. 11)26-29, 31, 33, 37-43, 45, 47. Overall, there was not a significantdifference in terms of control over the polymerization when using loweror higher T, different radical initiator or different feeding rate. Asexpected, reactions were faster with V-70, with higher T or fasterfeeding rate. The positive effect of feeding of radical initiator foracrylates is much higher than for MMA or St, discussed below. When nofeeding is applied (simulation 25a), polymerization is uncontrolled fornBA (high PDI), FIG. 1.

Conditions optimized using the computer software simulations were usedin experiments on 1 L scale. Results obtained during these experimentsfor nBA are reported below.

Example 2A Preparation of PnBA Via Starved Feeding ICAR ATRP

Four of the best polymerization conditions were chosen from the modelingstage and first tested in a 1 liter scale reactor. The experimental setup had one difference in comparison with MMA system; the reactor wasequipped with a cooling coil, needed for safety reasons—as reactionswith acrylates are more exothermic. As discussed in the background, weanticipate much less exothermic effects for the “starved” feedingmethod. The parameters that were adjusted are: temperature, targeted DP,feed rate of radical initiator, concentration of reagents, and amount ofCu catalyst.

Run: 08-006-57

Scale: 1 L reactor

Conditions: nBA/DEBMM/CuBr₂/TPMA/AIBN=2000/1/0.02/0.04/0.04 in bulk(anisole as internal standard), (10 ppm of Cu), T=90° C., time=7.5hours.

The rate of addition of the AIBN solution of 34.5 mg AIBN in 15 ml oftoluene was 2 ml/h, which is equivalent to adding 0.01 eq. AIBN/hcompared to the amount of ATRP initiator added. The initial volume ofliquid in the reactor was 840 ml. After 3 hour and 10 minutes anexothermic reaction was noted in the temperature profile and addition ofAIBN was stopped and cooling water started. Cooling was continued forone minute then stopped. The reaction temperature slowly returned to 90°C. and addition of the AIBN solution was resumed after 4 hours at areduced rate of 1 ml/h and no further exothermic reaction was observed.The reaction was stopped after 7½ hours.

The kinetics of the reaction and GPC results of the experiment are shownin FIG. 12 indicating that the final polymer had a DP of 700 and aM_(n(GPC)) 89,900 with a final PDI of 1.26.

The most critical observation was that the temperature of thepolymerization was well controlled and in contrast to the results shownin FIG. 1 this reaction was not excessively exothermic as a consequenceof the low absolute amount of AIBN added over the initial 3 hour periodand when the instantaneous concentration of initiator exceeded theconcentration of the formed CuBr₂/TPMA catalyst due to terminationreactions the resulting exotherm could be readily controlled by stoppingaddition of initiator. The slower rate of termination at higherconversion resulting from increased viscosity required slower rate ofaddition of AIBN. Therefore in this example it was determined that theconcept of “starved” feeding of an initiator did provide improvedcontrol.

Example 2B Polymerization of nBA

Polymerization conditions from simulation 37 were taken as a startingpoint for run 08-006-194 with feeding of V-70 at 70° C. Polymerizationwas very slow at the beginning (induction period) and after 2 h rate ofpolymerization significantly increased. Conversion reached 96% afteronly 4 hours reaction. This fast polymerization process was not wellcontrolled. Although molecular weights were close to theoretical values,PDI was high (>1.7) and did not decrease with conversion. The inductionwas also clearly visible on every simulation. These results suggest thata significant amount of initiator has to be consumed before there is anincrease in the rate of polymerization. Therefore in run 08-006-195 nBAa higher monomer to initiator ratio (DP=1000) was employed. It can beseen from FIG. 13 that control over the polymerization was significantlyimproved. As in the previous case, the kinetic plot was not linear butmolecular weights were close to theoretical values. GPC traces weremonomodal and shifting with reaction time. Molecular weight distributionof synthesized polymer decreased during the polymerization from PDI=1.78to 1.31. The induction period was around 5 h and after this time astrong exothermic effect was observed as shown in FIG. 14. Temperatureincreased from 70° C. to 110° C. The exothermic effect was controlled bystopping addition of V-70 to the reaction mixture. After stopping theaddition, polymerization stopped as well as any further increase oftemperature inside of the reactor.

This experiment proves that ‘feeding’ method is safe for exothermicpolymerization reactions. The control of the exothermic effect may be ofgreat importance in terms of safety as well as control over molecularweight, PDI and functionality of final polymer material.

Additional examples for polymerization of nBA also targeted a higher DPand a small amount of V-70 was added at the beginning of polymerizationprocess to reduce induction period. Polymerization of nBA with lower DPwas also repeated with higher amount of copper catalyst. In bothreactions a well controlled polymerization was observed.

Example 3 Polymerization of Styrene (St)

The polymerization of styrene via the new ‘feeding’ method for ICAR ATRPwas performed using the same strategy as for MMA monomer. Four of thebest polymerization conditions were chosen from the computer modelingstage and tested in a 1 liter scale reactor. After preliminary results,detailed in Table 2, were obtained additional experiments were performedwith improved conditions.

The parameters which were adjusted are: temperature, targeted DP, feedrate of radical initiator, concentration of reagents, and amount of Cucatalyst.

TABLE 2 Experimental conditions and properties of PSt prepared by ICARATRP with feeding of AIBN or thermal initiation.^(a) AIBN T Cu Feedingrate Time Conv. Run No. [° C.] St In [ppm] CuBr₂ Ligand AIBN [eq./h](Min) (%) M_(n,the0) ^(b) M_(n,GPC) M_(w)/M_(n) 08-006-185 120 100 1 500.005 0.1 0.0025 0 60 0.11 1100 1100 1.28 (old result) DEBMM TPMAThermal 120 0.20 2100 1700 1.27 initiation 240 0.36 3700 2800 1.27 5200.47 4900 3500 1.27 640 0.48 5000 3600 1.27 08-006-190 100 100 1 500.005 0.1 0 0.004 40 0.02 200 500 1.35 DEBMM TPMA (3.33 ml/h) 90 0.05500 900 1.28 180 0.12 1300 1400 1.25 300 0.27 2800 3200 1.20 630 0.565600 6100 1.16 08-006-192 100 100 1 50 0.005 0.1 0.005 0.008 30 0.101000 800 1.39 DEBMM TPMA (3.33 ml/h) 90 0.17 1700 1700 1.28 180 0.323300 2700 1.23 300 0.49 5100 4800 1.18 540 0.81 8400 7700 1.1508-006-193 100 1000 1 50 0.05 0.15 0.025 0.008 40 0.02 1600 2300 1.32DEBMM TPMA (3.33 ml/h) 90 0.04 4600 4700 1.19 200 0.10 10600 9200 1.15310 0.16 16600 14700 1.14 540 0.24 24500 20100 1.12 1240 0.25 2640020900 1.12 1300 0.26 27200 23300 1.11 1420 0.37 38100 25200 1.15 16000.46 47500 31900 1.15 1840 0.57 59500 37700 1.18 ^(a)polymerizationswere performed in bulk in 1 L reactor with overall volume of 850 ml andwith 5% of DMF as the internal standard; ^(b)M_(n,theo) = ([M]₀/[In]₀) ×conversion.

The polymerization kinetics were followed by measuring the rate ofdisappearance of monomer by gas chromatography (GC) and/or by nuclearmagnetic resonance (NMR). The synthesized polymers will be characterizedby gel permeation chromatography (GPC). Successful polymerization ofmonomer M should result in polymer P(M) with monomodal and narrowmolecular weight distribution (PDI<1.4). Molecular weight of thesynthesized polymers should be close to theoretical values as predictedfrom equation 2:M _(n,theo)=([M]₀/[R—X]₀)×conversion×M _(monomer).  2

Examples for Polymerization of St Using the Proposed Method

The computer model was build and then polymerization simulations wereperformed for styrene (St). Table 2 presents all of the results forpolymerization of St using ICAR ATRP with feeding of AIBN. In experimentWJ-08-008-190 St was polymerized in the presence of DEBMM as initiatorwith 50 ppm of CuBr₂ and excess of TPMA. Polymerization was carried at100° C. and AIBN was fed at 0.004 eq. vs. DEBMM per hour. Polymerizationreached 56% conversion in 10.5 h. Linear kinetics, were observed andmolecular weights were very close to the theoretical values. In thisexperiment PDI decreased during the reaction time from 1.35 to 1.16.Overall, the process was fully controlled.

In the second reaction, WJ-08-006-192, FIG. 15, a higher addition rateof AIBN was applied in order to accelerate rate of polymerization. Inaddition, a small amount of AIBN was added at t=0 to the reactionmixture in order to reduce most of Cu(II) to Cu(I) at the beginningstage of polymerization. Polymerization was almost two times fasterreaching 81% conversion in 9 hour. The kinetic plot has lineardependence and molecular weights are close to theoretical values. GPCtraces are monomodal and are shifting with reaction time. Molecularweight distribution of synthesized polymers decreased duringpolymerization from 1.39 to 1.15. This data proves that process wasfully controlled.

In final reaction reported in Table 2, reaction (WJ-08-006-193),polymerization of St was performed targeting a higher DP. St waspolymerized in the presence of DEBMM as initiator with 50 ppm of CuBr2and excess of TPMA. Polymerization was carried at 100° C. and AIBN wasfed at 0.008 eq. vs. DEBMM per hour. FIG. 16 shows kinetic plot for thisreaction. After 9 h the addition of AIBN was stopped and heating wasturned off. It can be seen from FIG. 16 that the polymerization processstopped immediately after stopping addition of the initiator. Thereactor was allowed to cool down overnight (no cooling system applied)and heated again after 21.6 h up to 110° C. At this time feeding of AIBNwas restarted with the same addition rate. It can be seen from thekinetic plot, FIG. 17 and molecular weights vs. conversion plot FIG. 16,that this reaction was restarted in fully controlled way.

Due to higher temperature in second phase of the reaction the rate ofpolymerization was higher. FIG. 16 also shows temperature inside as wellas outside of the reactor, thermocouples were placed insidepolymerization mixture and on the outer wall of the reactor. Thetemperature profile indicates good heat transfer as the difference intemperature from both thermocouples is similar and does not increase atany time during the reaction.

This set of data proves that the new ‘feeding’ process can be fullyautomated and that ICAR ATRP with controlled feeding can be successfullyapplied in synthesis of PSt with low as well high DP's.

Therefore in one embodiment of the invention we disclose how the rate ofdecomposition of the added free radical initiator is one factorcontrolling the rate of the CRP and the level of control over themolecular weight, molecular weight distribution and chain endfunctionality in the formed (co)polymer.

In another embodiment of the invention we disclose that if thetemperature of the reaction medium moves above the target temperatureand the addition of the initiator/reducing agent is terminated there isno further exotherm and once the temperature drops to the targettemperature the feeding of the initiator/reducing agent can be startedto reinitiate the polymerization reaction.

Another embodiment of the disclosed process is directed towardscontinuous control over the concentration of the persistent radical in aNMP. In this embodiment the rate of decomposition of the added initiatoris selected to match the rate of radical/radical termination reactionsthat would otherwise build up the concentration of the stable freeradical and reduce the rate of propagation.

A further embodiment of the disclosed process concerns RAFTpolymerizations. In a RAFT polymerization the rate of polymerization iscontrolled by the rate of added initiator. Normally all of the initiatoris added to the reaction at the beginning of the reaction and this couldlead to an increased rate of initiator decomposition if the temperatureof the reaction is not well controlled throughout the polymerizationvessel during each stage of the reaction.

In another embodiment of the invention a photoresponsive initiator isemployed and the rate of radical generation is controlled byintermittent controlled photostimulation.

What is claimed is:
 1. A polymerization process, comprising: i)introducing one or more free radically polymerizable monomers into asystem initially comprising: a) at least one transition metal catalyst;and b) an atom transfer radical polymerization initiator; and ii)polymerizing the one or more free radically polymerizable monomers byfeeding a free radical initiator into the system to regenerate the atleast one transition metal catalyst at a controlled rate to minimizeuncontrolled polymerization reactions; wherein the molar ratio of the atleast one transition metal catalyst to the atom transfer radicalpolymerization initiator is less than 0.10.
 2. The polymerizationprocess of claim 1, wherein the free radical initiator is continuouslyor intermittently fed into the system.
 3. The polymerization process ofclaim 1, wherein the at least one transition metal catalyst isintroduced into the system in a high or an oxidatively stable oxidationstate.
 4. The polymerization process of claim 3, wherein the freeradical initiator reduces the concentration of the higher oxidationstate transition metal present in the system.
 5. The polymerizationprocess of claim 1, wherein the free radical initiator reacts with ahigher oxidation state transition metal complex of the at least onetransition metal catalyst in a non-radical forming reaction.
 6. Thepolymerization process of claim 1, wherein the free radical initiatorreacts with a higher oxidation state transition metal complex of the atleast one transition metal catalyst in a non-ATRP initiator formingreaction.
 7. The polymerization process of claim 1, wherein the freeradical initiator is a photoresponsive radical initiator.
 8. Thepolymerization process of claim 1, wherein the process is a bulkpolymerization process, a biphasic polymerization process, an emulsionpolymerization process, a reverse emulsion polymerization process, or asuspension polymerization process.
 9. The polymerization process ofclaim 1, wherein the free radical initiator is2,2′-azobis(2-methylpropionitrile) (AIBN) or2,2′-azobis(4-methoxy-2.4-dimethyl valeronitrile) (V-70).
 10. Thepolymerization process of claim 1, wherein the feeding rate of the freeradical initiator is continuously or intermittently adjusted to allowconversion of the one or more polymerizable monomers to polymer toexceed 80%.
 11. The polymerization process of claim 1, wherein thefeeding rate of the free radical initiator is continuously orintermittently adjusted to maintain a targeted rate of polymerization.12. The polymerization process of claim 1, wherein the feeding rate ofthe free radical initiator is continuously or intermittently adjusted tomaintain a targeted temperature of the reaction.
 13. The polymerizationprocess of claim 1, wherein the one or more polymerizable monomerscomprises styrene, n-butyl acrylate, or methyl methacrylate.
 14. Thepolymerization process of claim 1, wherein the transition metal of theat least one transition metal catalyst is copper.
 15. The polymerizationprocess of claim 14, wherein the copper is present in an initial amountof at least 10 ppm.
 16. The polymerization process of claim 1, whereinthe at least one transition metal catalyst is CuBr₂.
 17. Thepolymerization process of claim 1, wherein the atom transfer radicalpolymerization initiator is diethyl 2-bromo-2-methylmalonate (DEBMM) or2-bromopropionitrile (BrPN).
 18. The polymerization process of claim 1,wherein the polymerization process is conducted at a temperature of 45°C. to 110° C.
 19. The polymerization process of claim 1, wherein thepolymerization process is a CRP process, an ICAR ATRP process, an ARGETATRP process, a RAFT process, or an NMP process.